4/3/2024 The Physiology of Muscles 1 The Physiology of Muscles Part April, 2023 BY Dr. Dereje Wakgari Objectives: Know the major classes of muscles of the body. Describe the molecular basis of muscle contraction. Differentiate the roles of Ca2+ in skeletal, cardiac + smooth muscles. The Physiology of Muscles Introduction Part III 1. Introduction 1.1. General Points a. Can be excited chemically, electrically + mechanically. b. Contractile mechanisms (actin + myosin) that can be activated by AP. 1.2. Mass a. 45-50% of the total body mass ( 600 muscles) b. 40% skeletal muscles + 10% cardiac and smooth muscles (45-50%). 4/3/2024 The Physiology of Muscles 4 The Physiology of Muscles Introduction Part III 1.3. O2 consumption a. 25% total bodily O2 consumption at rest is consumed by the muscles. b. During strenuous exercise this amount can increase as much as 10-20 times. 2. Types/Classification 2.1. Anatomical 2.1.1. Striations: Presence of alternating light and dark bands on the sarcolemma. 4/3/2024 The Physiology of Muscles 5 The Physiology of Muscles Introduction Part III Classification 4/3/2024 The Physiology of Muscles 6 The Physiology of Muscles Introduction Part III 2.1.1.1. Skeletal muscle i. Have well developed cross striations (interdigitating thick and thin filaments). ii. Voluntary muscle tissue. iii. Cells are long and multinucleated. iv. Contract only in response to stimuli (no syncytial bridges between cells). 4/3/2024 The Physiology of Muscles 7 The Physiology of Muscles Introduction Part III 2.1.1.2. Cardiac muscle i. Have cross striation (banding pattern of thick and thin filaments). ii. Involuntary muscle tissue. iii. Cells are branched and mononucleated. iv. Have intercalated disc with gap junctions. 2.1.2. Non-striations/Smooth Muscle Alternating dark and light bands are absent. 4/3/2024 The Physiology of Muscles 8 The Physiology of Muscles Introduction Part III 2.1.2.1. Single unit smooth muscle (Visceral smooth muscle) i. Are large sheets of mononucleated small cells. ii. Have low resistance bridge of gap junctions. iii. Show synchronous excitation and contractions. (= functional syncytium) iv. Have unstable resting membrane potential. v. Found in gut, ureter, small blood vessels and uterus. 2.1.2.2. Multiunit smooth muscles i. Found in iris, lungs, hair roots and large arteries. ii. Have no gap junctions but each cell receive ANS nerve terminal. 4/3/2024 The Physiology of Muscles 9 The Physiology of Muscles Introduction Part III 2.2. Physiological 2.2.1. Voluntary Muscle • Skeletal muscle (CNS, somatic neurons). 2.2.2. Involuntary muscle • Cardiac muscle (Intrinsic + Extrinsic factors, ANS + Hormonal) • Smooth muscle (Intrinsic + Extrinsic factors, ANS + Hormonal) 4/3/2024 The Physiology of Muscles 10 The Physiology of Muscles Skeletal Muscle Part III 3.0. Skeletal Muscle • Interactions between the body and the external environment (maintenance of posture and movement, speech, respiration…). 3.1. Physiological classifications 3.1.1. Type I: Slow twitch oxidative fibers (red muscle) i. Have slow myosin ATPase activity. ii. High myoglobin content iii. Many mitochondria and capillary iv. Resistant to fatigue, high oxidative capacity v. Muscles of the back and neck (strong gross sustained movt.) 4/3/2024 The Physiology of Muscles 11 The Physiology of Muscles Skeletal Muscle Part III 3.1.2. Type IIA: Fast oxidative-glycolytic fibers (red fibers) i. Fast myosin ATPase activity ii. Fatigable fibers iii. Use glycolytic and oxidative ATP sources 3.1.3. Type IIB: Fast glycolytic fibers (white muscles) i. Fast velocity of contraction ii. Fast myosin ATPase activity iii. Glycolysis is the main ATP source iv. Few myoglobin, mitochondria and blood vessels are present. v. Muscles of the hand extraocular muscles (fine, rapid, precise movt.) 4/3/2024 The Physiology of Muscles 12 Structural arrangement and contractile unit 13 14 Structural arrangement and contractile unit 15 Structural arrangement and contractile unit 16 Structural arrangement and contractile unit The Physiology of Muscles Skeletal Muscles Part III 3.2. Structural arrangement and contractile unit Muscle ↓ epimysium Fasciculus (20 muscle fibers) ↓ perimysium Muscle fiber (ɵ=10-100 µm, L=30cm, multinucleated) ↓ endomysium (Sarcolemma, sarcoplasm/myoplasm Sarcoplasm reticulum Myofibril (ɵ= 1-2µm, longitudinal, Sarcomere, 75% muscle vol., Z-line, α-actinin, desmin) Myofilaments Thick filaments 1500 molecules, myosin 4/3/2024 The Physiology of Muscles Thin filaments 3000 molecules, actin 17 The Physiology of Muscles Skeletal Muscles Part III Terms 1. Epimysium: a connective tissue which ensheaths the entire muscle. 2. Perimysium: a connective tissue that ensheaths the fascicles 3. Endomysium: a sheath that covers each muscle fiber. • Each one is the continuation of the other. 4. Sarcoplasmic Reticulum: a tubular network that divides the individual skeletal muscle fiber into myofibrils. 5. Sarcolemma: a true plasma membrane of skeletal muscle fiber. 6. α-actinin: a protein that connects actin to the z-line. 7. Myoplasm/sarcoplsam: cytoplasm of the muscle cell. 4/3/2024 The Physiology of Muscles 18 The Physiology of Muscles Skeletal Muscles Part III 8. Desmin: a protein that links adjacent myofibrils, binding z lines to plm 9. Myosin: the thick contractile protein. 10. Actin: the thin contractile protein. 11. Dystropin: actin binding protein linking transmembrane protein, βdystroglycan, in the sarcolemma with cytoplasmic protein syntrophins (α-dystroglycan, (sarcoglycan, α, β, γ, δ)) 12. Titin: tethers myosin to z lines, serves as a scaffold for sarcomere. (prevents overstretching of sarcomere, ?cell signaling? Stretch sensor, Titinopathies) 13. Nebulin: a template protein which determines the precise size of actin 4/3/2024 The Physiology of Muscles 19 Geometrical orientation of the contractile elements 20 21 Geometrical orientation of the contractile elements The Physiology of Muscles Skeletal Muscles Part III 3.3. Functional unit (Sarcomere) a. It is the distance between two z-lines. b. Responsible for the striated appearance. 3.3.1. Dimensions a. The resting length of a sarcomere is 2µm-2.2µm. b. At this length it generates the greatest force of contraction. 4/3/2024 The Physiology of Muscles 22 The Physiology of Muscles Skeletal Muscles Part III 3.3.2. Molecular geometry • Differences in Refractive indices When viewed under polarized light. A-Band (A= Anisotropisch)* a. The darker area in the centre of the sarcomere. b. It is due to the orderly arrangement of thick filaments. c. Thin filaments may extend into the A-band. H-Band (H = Hensen’s disc, ?Hell?) a. It contains only myosin tails (no myosin heads/no cross-bridges) b. There are no thin filaments. c. When the muscle is relaxed 4/3/2024 * Germanic words The Physiology of Muscles 23 The Physiology of Muscles Skeletal Muscles Part III M-line (M= Mittelmembran) a. Site of the reversal polarity of the myosin molecules in each of the thick filaments. b. It vertically bisects the H-Band c. It contains 2 important proteins: • Myomesin: a structural protein that links neighboring thick filaments • Creatinine Phosphokinase: an enzyme that maintains adequate ATP conc. in working muscle fibers. 4/3/2024 The Physiology of Muscles 24 The Physiology of Muscles Skeletal Muscles Part III I-Band (I= Isotropisch) a. The lighter area on either side of the z-lines. b. Each sarcomere contain half of the two I-bands. Z-Line/Disc (Z = Zwischenscheibe) a. Dense line in the center of each light band. b. Separates one sarcomere from the next. c. It is the attachment site for the thin filaments. 4/3/2024 The Physiology of Muscles 25 The Physiology of Muscles Skeletal Muscles Part III NB 1. During muscular contraction: a. There is NO CHANGE in length of either the thick or the thin filaments. b. H-zone disappears and Z-line gets considerably darker. c. There is shortening of the sarcomere (↓ I-band and H zone, and A-band remains κ) 2. a. When a muscle increases its length → ↑ in the No of sarcomeres (NOT the length of each sarcomere) b. The length of thick & thin filaments of sarcomeres is identical in a neonate & in the adult muscle. 4/3/2024 The Physiology of Muscles 26 The Physiology of Muscles Skeletal Muscles Part III 3.4. Molecular Basis of Contraction 3.4.1. Sliding-Filament Model (Hanson & Huxley, 1955) This model theorizes that sliding in of the filaments (thick & thin) toward the center of muscle and sarcomere is responsible for the shortening and force of contraction. 4/3/2024 The Physiology of Muscles 27 The Physiology of Muscles Skeletal Muscles Part III 3.4.2 Thick Filament a. It is called myosin (an actin-binding protein). b. Dimensions: ɵ = 11-18 nm, L = 1.6 µm c. Composition of Myosin: 4/3/2024 The Physiology of Muscles 28 The Physiology of Muscles Skeletal Muscles Part III 3.4.3. Thin Filaments a. They are called actin c. Components : 1. Globular proteins i. Actin ii. Troponin (50 molecules) 2. Non-Globular proteins: tropomyosin (40-60 molecules, 70kD) 4/3/2024 The Physiology of Muscles 29 The Physiology of Muscles Skeletal Muscles Part III 3.4.4 Regulatory proteins A. Tropomyosin a. It blocks the binding sites of myosin on actin. B. Troponins ~ Small globular units located at intervals along the tropomyosin molecules. 4/3/2024 The Physiology of Muscles 30 31 Actins, Troponins and Tropomyosin Filaments The Physiology of Muscles Skeletal Muscles Part III b. Contractile state: • The invading action potential to T-Tubule → Ca2+ released from SR → binds to troponin C → binding of troponin I to actin is weakened → tropomyosin moves laterally → uncovers binding sites for myosin heads → contraction (in the presence of ATP). 4/3/2024 The Physiology of Muscles 32 The Physiology of Muscles Skeletal Muscles Part III 3.5.2. Regulatory action of calcium 2 tubular networks (Sarcotubular system) that are involved with Ca2+: Transverse Tubule (T-tube) Sarcoplasm Reticulum (SR) . Functions: i. Stores Ca2+ in the terminal cisternae (lateral sacs, 1calsequestrin = 43 Ca2+ ) ii. Uptake and release of Ca2+ NB Calsequestrin is sarcoplasmic protein that binds Calcium. 4/3/2024 The Physiology of Muscles 33 The Physiology of Muscles Skeletal Muscles Part III 3.5.3. Regulation of ATP a. Actin + myosin + ATP + Ca2+ → CONTRACTION b. Actin + myosin + ATP - Ca2+ → RELAXATION c. ATP is needed for relaxation e. 3 ATP molecules are needed: i. For the formation of the actinmyosin complex ii. For the initiation of relaxation. iii. To pump out Ca2+ from the sarcoplasm to sequester it into the SR (Ca2+ - Mg2+ pump) 4/3/2024 The Physiology of Muscles 34 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.1. Excitation-Contraction Coupling/ Electromechanical Coupling Def. ~ is the process of linking ∆Em/AP to muscle contraction. • Electrical events precedes mechanical events (2ms, 100ms) • Twitch 4/3/2024 The Physiology of Muscles 35 The Physiology of Muscles Skeletal Muscles: ECC Part III Motor Unit 36 Motor Units 37 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.2. Events at the neuromuscular junction: 3.6.2.1. Presynaptic end (α-motor neuron) AP in presynaptic α-motor neuron terminals Depolarization of plasma membrane of the presynaptic α-motor neuron axon terminals [Δ 30mV] Opening of Ca2+ channels at the active zones →↑Ca2+ permeability and entry of Ca2+ into α-motor neuron axon terminals Release of Ach from the synaptic vesicles into the synaptic cleft (200-300 vesicles/exocytosis) 4/3/2024 The Physiology of Muscles 38 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.2.2. Postsynaptic end Diffusion of Ach to Postjunctional membrane → combination of Ach with nAchR (107-108, 2α subunit) on the motor endplate Conformational change → opening of the gate→↑ permeability of the postjunctional membrane to Na+ and K+ Transient change in the Em→ depolarization → EPP Depolarization of areas of muscle membrane adjacent to endplate and initiation of AP 4/3/2024 The Physiology of Muscles 39 The Physiology of Muscles Skeletal Muscles: ECC Part III Endplate Potential/EPP i. A graded response (magnitude of depolarization α No of open Ach channels ii. Transient (∵Ach is hydrolyzed to form choline and acetate). iii. Amplitude: 50mV iv. No voltage-gated Na+ and K+ channels at the endplate region (∴ No AP, Na+, K+ channels are located on the muscle membrane contiguous to the endplate) 4/3/2024 The Physiology of Muscles 40 The Physiology of Muscles Skeletal Muscles: ECC Part III v. Ionic basis of EPP: • Ach activated channel • Independent of membrane potential • Em is between EK+ and ENa+ vi. EPP depolarizes the contiguous membrane regions by electronic conduction to threshold and AP is generated. 4/3/2024 The Physiology of Muscles 41 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.3. Propagation of AP into the T-tubule & release of Ca2+ from the terminal cisternae A. Transverse Tubule (T-tubule) i. It is an invagination of the surface of the sarcolemma ii. It is found at the junction of A-I bands (at z-line in frog) iii. One end of the tube is open to extracellular space, but its other end is closed. iv. Function: rapid transmission of AP from the cell membrane to all the fibers on the muscle. 4/3/2024 The Physiology of Muscles 42 The Physiology of Muscles Skeletal Muscles: ECC Part III B. Sarcoplasm Reticulum (SR) i. It is an internal tubular structure that runs between the myofibrils. ii. It is closed at both ends. iii. It is not continuous with the sarcolemma. iv. Functions: • Stores Ca2+ in the terminal cisternae (lateral sacs) • Uptake and release of Ca2+ NB • Calsequestrin is sarcoplasmic protein that binds Ca2+ (1 calsequestrin = 43 Ca2+ ) • Triad: 2 lateral sacs + 1 transverse tubule 43 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.4. The Activation of Muscle Proteins 3.6.4.1. Thick Filaments a. Myosin (an actin binding protein) b. 2 distinct structures: • Myosin head (cross bridge): actin-binding site • ATP binding site (ATPase): hydrolyzes ATP 3.6.4.2. Thin Filaments a. Actins 4/3/2024 The Physiology of Muscles 44 The Physiology of Muscles Skeletal Muscles: ECC Part III b. Troponins: Small globular units located at intervals along tropomyosin molecules. i. Troponin T: it binds other troponin components to tropomyosin ii. Troponin I: inhibits the interaction of myosin with actin iii. Troponin C: it has the binding site for Ca2+ that initiates contraction Tropomysoin i. A rod-shaped molecule stretched along each strand of thin filament. ii.1 tropomyosin molecule covers seven actin monomers iii. It blocks the binding sites of myosin on actin. 4/3/2024 The Physiology of Muscles 45 46 47 The Physiology of Muscles Skeletal Muscles:ECC Part III Resting state i. Interaction of thick and thin filaments is inhibited ii. Troponin I & tropomyosin covers the sites where myosin heads bind to actin Activated States: Influx of Ca2+ ↓ Binds to Troponin C (4 Ca2+) ↓ Conformational change in troponin ↓ Tropomyosin moves aside ↓ Exposes the myosin-binding sites on actin ↓ Myosin cross-bridge on the thick filament is exposed to actin filaments 48 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.5. Generation of Tension Cross-bridge cycle: 4 steps 1. Binding of the cross-bridge to actin A+M* . ADP. Pi A.M* + ADP + Pi Actin binding 2. Bending of the cross-bridge producing movement of thin filament. A. M*. ADP. Pi A.M*.+ ADP + Pi Cross-bridge movement 3. Detachment of the cross-bridge from the thin filament A.M+ ATP A+ M.ATP Cross-bridge dissociation from actin 4. The cross-bridge returns to its original upright position to repeat the cycle. M.ATP M*. ADP. Pi ATP hydrolysis NB. Tension is generated by repetitive cross-bridge cycling. 49 50 51 The Physiology of Muscles Skeletal Muscles: ECC Part III 3.6.6. Relaxation of Muscle. a. Removal of Ca2+ from the Myoplasm (<0.1µmol/l) into the SR. b. For Ca2+ removal from the sarcoplasm the third ATP is consumed by Ca2+-Mg2+ -ATPase c. After removal of Ca2+ : i. Troponin returns to its original conformational state. ii. Tropomyosin inhibition of Myosin-Actin interaction is restored. iii. Cross-bridge cycling stops and the muscle is returned to its resting state. d. Breakdown of Ach by AchE. 4/3/2024 The Physiology of Muscles 52 The Physiology of Muscles Skeletal Muscles: ECC Part III Regulatory function of ATP i. Actin + Myosin +ATP + Ca2+ Contraction ii. Actin+ Myosin + ATP – Ca2+ Relaxation iii. In the absence of Ca2+ ATP is not hydrolyzed. iv. 3 ATP molecules are needed: a. For energizing the myosin cross-bridges b. For dissociation of actinmyosin complex and initiation of relaxation c. To pump out Ca2+ from the sacroplasm to sequester it into the SR (Ca2+-Mg2+ - pump) 4/3/2024 The Physiology of Muscles 53 The Physiology of Muscles Skeletal Muscles: ECC Part III Changes a. Banding • • • • 4/3/2024 H-zone: Z-line: I-band: A-band: Disappears Gets considerably darker Narrower/smaller κ b. Contractile proteins: NO CHANGE in length of myosin or actin c. Sarcomere: Shortens The Physiology of Muscles 54 The Physiology of Muscles Skeletal Muscles: ECC Part III Ion channels involved: i. Voltage-gated Ca2+ channels (active zone, α-motor neuron) ii. Ligand-gated cationic channels (Ligand-gated Na+ channels, motor endplate) iii. Voltage-gated Na + channel (contiguous to the motor endplate). iv. Voltage-gated Ca2+ channel (t-tubule) v. 4/3/2024 RyR Ca2+-release channel (SR) The Physiology of Muscles 55 The Physiology of Muscles Skeletal Muscles: ECC Part III Summary Discharge of motor neuron ↓ Release of Ach at motor endplate ↓ Binding of Ach to nAchR ↓ ↑gNa+ and gK + in endplate membrane ↓ Generation of EPP ↓ Generation of AP in muscle fibers 4/3/2024 The Physiology of Muscles 56 The Physiology of Muscles Skeletal Muscles: ECC Part III Generation of AP in muscle fibers ↓ Inward spread of depolarization along T-tubules ↓ Release of Ca2+ from terminal cisterns of SR and diffusion to thick and thin filaments ↓ Binding of Ca2+ to troponin C, uncovering myosin-binding sites on actin ↓ Formation of cross-linkages between actin and myosin and sliding of thin on thick filaments, producing movement 4/3/2024 The Physiology of Muscles 57 The Physiology of Muscles Skeletal Muscles: ECC Part III Steps in relaxation Ca2+ pumped back into SR ↓ Release of Ca2+ from troponin ↓ Cessation of interaction between actin and Myosin 4/3/2024 The Physiology of Muscles 58 The Physiology of Muscles Skeletal Muscles: Clinical correlates Part III Rigor Mortis a. It is a state of muscle contracture, ie., contraction produced without AP and not followed by relaxation. b. It is a contracture which occurs in the muscles after death. It starts in small muscles (2-3hrs) after death and involves all muscles in 12 hrs. c. The rigidity is due to depletion of ATP from the muscle. Calcium diffuses out of the SR & can not be recollected by the Calcium pump. d. Calcium initiates muscle contraction using the remaining ATP molecules, relaxation does not occur because calcium is not recollected back into the SR, and no ATP is available to disconnect the myosin heads from actin. 4/3/2024 The Physiology of Muscles 59 The Physiology of Muscles Skeletal Muscles: Clinical correlates Part III e. It disappears when muscle fibers are autolysed by lysosomal enzymes released after death. f. It starts to disappear 14hrs after death and completed in 24hrs. High environmental temperature accelerates the appearance and disappearance of rigor mortis. g. The extent of rigor mortis is used medically to determine the time of death. 4/3/2024 The Physiology of Muscles 60 The Physiology of Muscles Cardiac Muscle Part III 4.2. Cardiac Muscle Vs Skeletal Muscle 4.2.1. Cardiac Muscle. 1. A cardiac myocyte has a single nucleus which is smaller (ɵ = 15-20 µm, L = 100µm) 2. Has abundant amount of mitochondria (30%) + myoglobin which makes it fatigue resistant (myoglobin facilitates the transport of oxygen from the sarcolemma to the mitochondria) 3. A cardiac cells are joined end-to-end by intercalated discs: i. Attach one cell to the next by means of desmosomes ii. Connect the thin filament of the myofibrils of adjacent cells. (Mechanical + electrical coupling) 4/3/2024 The Physiology of Muscles 61 62 The Physiology of Muscles Cardiac Muscle 4/3/2024 Part III The Physiology of Muscles 63 The Physiology of Muscles Cardiac Muscle Part III iii. Contain gap junctions which is synchronizing the contractions of heart muscle cells. 4. The T-tubule is larger and it is found at z-line 5. The SR - makes contact with T-tubule and the cell membrane. 4/3/2024 The Physiology of Muscles 64 The Physiology of Muscles Cardiac Muscle Part III 4.3. Excitation-Contraction Coupling/Electrochemical Coupling (Cardiac Vs Skeletal) 4.3.1. Cardiac Muscle. 1. Ca2+- release from the SR is triggered by Ca2+ (not by membrane Depolarizations). (Extracellular Ca2+ →SR (is responsible for prolonged plateau phase). 2. T-Tubule (DHPR) contains Ca2+ channel (through which Ca2+ enters the cell during the AP). 3. SR-RyR containing Ca2+- release channel is opened by influx of Ca2+ from the T-Tubule. 4/3/2024 The Physiology of Muscles 65 66 67 The Physiology of Muscles Cardiac Muscle Part III 4. Amount of Ca2+- release from the SR in under physiologic control. a. Hormones (catecholamines) → ↑ the amount of Ca2+ entering the cell → ↑IC Ca2+ b. Pump (Na+-Ca2+ Exchanger, ↑1Ca2+, ↓3Na+) is increasing the Ca2+ in the cell. Clinical correlates • Familial cardiomyopathic hypertrophy • Hypertrophy 4/3/2024 The Physiology of Muscles 68 69 The Physiology of Muscles Smooth Muscles Part III 5.0. SMOOTH MUSCLE 5.1. Introduction a. It is important in regulation of the airways, blood vessels, GIT, and hollow organs (bladder, uterus...) b. It is controlled by intrinsic factors (inherent rhythmicity): ANS + HORMONES. c. It produces slower and longer-lasting contractions (slow and sustained) (↓rates of cross-bridge cycling → LATCH STATE → maintain TONE and little energy consumed) 4/3/2024 The Physiology of Muscles 70 The Physiology of Muscles Smooth Muscles Part III 71 The Physiology of Muscles Smooth Muscles Part III 72 73 The Physiology of Muscles Smooth Muscles Part III 5.2. Smooth Muscle Vs Striated Muscle. 5.2.1. Smooth Muscle. 1. It has NO STRIATIONS (sparse thick filaments and absence of transverse registration). 2. Has elongated spindle shaped cells with a single nucleus (L = variable size, attached in series to bear equal stress). 3. Sarcomeres are absent. 4/3/2024 The Physiology of Muscles 74 The Physiology of Muscles Smooth Muscles Part III 4. The myofilaments are : a. Thick filaments: myosin b. Thin filaments: actin and tropomyosin (No troponin) c. Thick and thin filaments are dispersed through out the cell. They are not arranged in strictly ordered pattern. d. Thin filaments are attached to dense bodies (functional equivalents of Z) i. DENSE BODIES: are found in cell membrane and cytoplasm composed of -actinin. 5. Tubules: T-tubules are absent and the SR is rudimentary 4/3/2024 The Physiology of Muscles 75 The Physiology of Muscles Smooth Muscles Part III 5.3. Excitation - Contraction Coupling (Smooth M.Vs Striated M.) • Cross-bridge cycling is regulated by Ca2+- induced phosphorylation of myosin. 1. Myosin cross-bridge has 4 light chain 2. Myosin can not bind to actin unless one of these light chains (LC20) is phosphorylated. 4/3/2024 The Physiology of Muscles 76 The Physiology of Muscles Smooth Muscles Part III a. Phosphorylation of LC20 is by Myosin Light Chain Kinase (activated by Calmodulin, 4Ca2+, Kinase - calmodulin - Ca2+- complex) b. Ca2+ can enter the cell in a variety of ways: i. Stimulation by a neurotransmitter (receptor-activated Ca2+ channel) ii. Voltage-operated Ca2+channels iii. Release from SR (SR-IP3R) (IP3R = inositol triphosphate receptors) 3. The light chains are dephosphorylated by the enzyme Myosin Light Chain Phosphorylase. 4/3/2024 The Physiology of Muscles 77 The Physiology of Muscles Smooth Muscles Part III 78 79 80 81 82 83 84 85 86 Summary ECC smooth muscle Binding of Ach to mAchR ↓ Increased Ca2+ influx into the cell ↓ Activation of calmodulin-dependent myosin light chain kinase ↓ Phosphorylation of myosin ↓ Increased myosin ATPase activity and binding of myosin to actin ↓ Contraction ↓ Dephosphorylation of myosin by myosin light chain phosphatase ↓ Relaxation, or sustained contraction due to the latch bridge and other mechanisms 87 • Thank you
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